The clinical manifestations of Chlamydia trachomatis range from asymptomatic infections of mucosal surfaces to severe disease that results in blindness, infertility, ectopic pregnancy, and perhaps arthritis. Much of the damage resulting from chlamydial infection has been attributed to an overzealous immune response that limits replication of the organism and concurrently destroys host tissues. The exact nature of the protective and deleterious host responses against chlamydia remain uncharacterized. Similarly, cytokine inducible nitric oxide (NO) has been found to limit the replication of chlamydia in vitro and to play a protective role in host defense against other intracellular pathogens in vivo. It also is as an immunopathogenic effector molecule in several in vitro and in vivo systems. Its exact role in immune responses against chlamydia in vivo has yet to be delineated. In studies preliminary to this proposal, we assessed NO production in a well- characterized murine model of chlamydial genital tract infection with the mouse biovar of Chlamydia trachomatis. We found profound strain differences in the induction of NO and in the course of infection in different strains of mice. An inverse correlation between NO production and susceptibility to infection was observed. Because of the parallels between this model and other mammalian models of NO-mediated intracellular pathogenesis, we propose to study NO production following chlamydial genital tract infection of mice and its role as a potential protective or pathogenic molecule. To accomplish this, we first propose experiments which will further characterize the kinetics of urinary nitrate excretion (an end product of NO production) in various susceptible and resistant strains of mice. This will be correlated with the course of infection, the development of inflammatory tissue damage in the uterus and oviduct, hydrosalpinx formation, and the development of infertility. These experiments will be followed by those which directly assess the role of NO in either protective immune responses or in damaging inflammation by inhibiting the production of NO in vivo with specific chemical inhibitors of the cytokine inducible nitric oxide synthase. If NO functions in a protective capacity, the infection course will be prolonged or chronic when NO is inhibited. If it plays a major role in tissue destruction, then tissue damage and the resulting infertility will be reduced when it is inhibited. It is the purpose of the proposed experiments to characterize the role of NO in this model and lead to more detailed projects that elaborate the molecular and biochemical mechanisms of NO-mediated pathogenesis in chlamydial disease states.